Hypoglycemic compositions containing benzhydryl-lactamimide derivatives

ABSTRACT

Pharmaceutical compositions with hypoglycemic and diuretic properties and methods for their use are disclosed herein. The active ingredients of the compositions are compounds of the formula   WHEREIN R is hydrogen or lower alkoxy of from one to six carbon atoms, and when R represents lower alkoxy the substituent alkoxy radical may be attached at the ortho-, meta- or para-position of the phenyl radical; R1 is hydrogen or lower alkyl of from one to four carbon atoms; n is a whole integer of from 3 to 11; or pharmaceutically acceptable acid addition salts of said compounds and individual optical isomers where applicable.

United States Patent mi Grisar et al.

[ll] 3,783,1b2

[ Jan.1,1974

[ HYPOGLYCEMIC COMPOSITIONS CONTAINING BENZHYDRYL-LACTAMIMIDEDERIVATIVES [75] Inventors: Johann Martin Grisar; Thomas R.

Blohm, both of Cincinnati, Ohio [73] Assignee: Richards0n-Merrelllnc.,New York,

[22] Filed: Sept. 13, 1971 [21] Appl. No.: 180,118

[52] US. Cl 424/267, 424/244, 424/274 [51] Int. Cl A6lk 27/00 [58] Fieldof Search 424/267 [56] References Cited OTHER PUBLICATIONS ChemicalAbstracts 72: 13251 lp (1970). Chemical Abstracts 75: 20l83p (1971).

Primary Examiner.lerome D. Goldberg Attorney-Eugene O. Retter et a].

"('57 ABSTRACT Pharmaceutical compositions with hypoglycemic anddiuretic properties and methods for their use are disclosed herein. Theactive ingredients of the compositions are compounds of the formulawherein R is hydrogen or lower alkoxy of from one to six carbon atoms,and when R represents lower alkoxy I the substituent alkoxy radical maybe attached at the 7 Claims, N0 Drawings IIYPOGLYCEMIC COMPOSITIONSCONTAINING BENZIIYDRYL-LACTAMIMIDE DERIVATIVES FIELD OF INVENTION Thisinvention relates to pharmaceutical compositions with hypoglycemic anddiuretic properties containing benzhydryllactamimide derivatives as theactive ingredient, and to the use of such compositions.

SUMMARY OF INVENTION It has been found that compounds of the followingformula, or pharmaceutically acceptable acid addition salts of saidcompounds and individual optical isomers where applicable, are useful ashypoglycemic and diuretic agents:

R Formula I DISCUSSION OF THE PRIOR ART Compounds of Formula I where Ris hydrogen, R is lower alkyl and n is an integer from 3 to 5 andprocesses for the preparation thereof are disclosed in French Pat. No.1,576,111 of McNeil Laboratories Inc., published on July .17, 1968, andCanadian Pat. No. 850,116 of McNeil Laboratories Inc., issued on Aug.25, 1970. In the Canadian patent some of these compounds are stated topossess antiinflammatory activity and central nervous system depressantactivity. There is no disclosure of these compounds being useful ashypoglycemic or diuretic agents.

DETAILED DESCRIPTION OF INVENTION For convenience and uniformity all ofthe compounds of this invention are named and represented by Formula l.It is known, however, that compounds of this type as acid addition saltsmay also be represented by the tautomeric form illustrated by thefollowing Formula II:

N anion- R FormulaII This tautomerism has been discussed by R. Kwok andP. Pranc, J. Org. Chem. 32, 740 (1967). Structures of this formula couldbe named differently. In solution,

under the conditions of the therapeutic utility, the proportion of eachtautomeric form, or the delocalization of the charge between the twonitrogen atoms, will be dependent upon numerous factors including thenature of the substituents, the pH of the medium, and the like. Thisequilibrium state is conveniently depicted by the following Formula 111:

R Formula III Preferred active ingredients of the compositions of thisinvention are compounds of the formula Formula IV wherein R has themeaning given hereinbefore and n is a whole integer of from 3 to 7. Themore preferred active ingredients of the compositions of this inventionare compounds of Formula IV wherein R is hydrogen and n is a wholeinteger of from 3 to 5.

As examples of lower alkyl radicals that R may represent in Formulas I,II and III there may be mentioned, for example, methyl, ethyl, propyl,isopropyl, butyl, tertiary butyl and the like.

As examples of lower alkoxy radicals that R may represent in Formulas I,II, III and IV there may be mentioned, for example, methoxy, ethoxy,propoxy, butoxy, pentyloxy and the like.

Pharmaceutically acceptable acid addition salts of the base compounds ofthis invention are those of any suitable inorganic or organic acids.Suitable inorganic acids are for example, hydrochloric, hydrobromic,sulfuric or phosphoric acids and the like. Suitable organic acids are,for example, carboxylic acids such as acetic, propionic, glycolic,lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic,cinnamic, salicylic, 2-phenoxybenzoic and the like, or sulfonic acidssuch as methane sulfonic, 2- hydroxyethane sulfonic acid and the like.

As examples of compounds of this invention there may be mentioned, forexample, Z-(diphenylmethylimino)hexahydroazepine hydrochloride,hexahydro-2-[ (a-phenyl-p-methoxybenzyl)imino lazepine hydrochloride,

2-[ (diphenylmethyl)imino 1 -methylpiperidine hydrochloride,

2- (diphenylmethyl )imino ]octahydroazocine hydrochloride, 2-[(diphenylmethyl)imino]octahydroazonine hydrochloride,

3 2-[(diphenylmethyl)imino]-l-methylpyrrolidine drochloride,2-[(diphenylmethyl)imino]pyrrolidine hydrochloride,2-[(diphenylmethyl)imino]piperidine hydrochloride,hexahydro-2-[(m-methoxy-a-phenylbenzyl)imino]azepine hydrochloride,hexahydro-2-[(o-methoxy-a-phenylbenzyl)imino]azepine hydrochloride2-[(p-butoxy-a-phenylbenzyl)imino]hexahydroazepine hydrochloride,2-[(p-methoxy-a-phenylbenzyl)imino]piperidine drochloride,2-[(p-ethoxy-a-phenylbenzyl)imino]octahydroazomne,2-[(diphenylmethyl)imino]-1- propyloctahydroazocine,2-[(diphenylmethyl)imino]azacyclotridecane chloride,

2-[ (diphenylmethyl )imino 1 -methylhexahydroazepine acid maleate, andthe like.

It has been found that the compounds of this invention are useful ashypoglycemic and diuretic agents and can be used in the form ofpharmaceutical preparations suitable for oral or parenteraladministration. The quantity of compound in the unit dosage can varyover a wide range to provide from about 1.0 mg/kg to about 100 mg/kg ofbody weight of the patient per dose to achieve the desired effect. Thedesired effect can be obtained by consumption of 25 to 500 mg of theactive ingredient taken 1 to 4 times daily. The compounds of thisinvention can be administered to warm blooded animals and particularlyto mammals.

The novel compounds, together with conventional pharmaceutical carrierscan be employed in unit dosage forms such as solids, for example,tablets or capsules or liquid solutions, suspensions or elixirs for oraladministration and injections, or liquid solutions, suspensions,emulsions and the like for parenteral use. The quantity of activeingredient in each dosage will gener ally differ depending on the typeof unit dosage, the type of animal and its weight. Thus, each dosage cancontain from about 25 mg to over 500 mg of active ingredients in asignificant quantity of pharmaceutical carrier.

As hypoglycemic agents, the compounds of this invention may be used tocontrol hyperglycemic conditions such as occurs in diabetic patients. Toillustrate the hypoglycemic activity of the compounds of this inventionmale rats of the Charles River C.D. strain each weighing from 120 to 140grams were fasted for hours then injected subcutaneously with 1 g/kg ofbody weight of glucose in 0.5 ml of 0.9 percent NaCl. Immediatelyfollowing the glucose injection the animals were administered by oralintubation a compound of this invention in 0.5 ml of carboxymethylcellulose. Two hours after the test compound was administered blood waswithdrawn from the animals and a quantitative analysis of glucose in theplasma was performed by use of the ultramicro glucose oxidase procedureas described by L.P. Cawley et al., Am. J. Clin. Path. 32, 195-200(1959). Animals receiving carboxymethyl cellulose with no test compoundserved as a control. The results of this test are summarized in thefollowing Table l.

hydro- TABLE I Reduclion in Dosage Plasma Test compound mg/kg Glucosefrom Control 2-[(Diphenylmethyl)imino]- 6.25 I l pyrrolidinehydrochloride 12.5 24 25 42 50 33 I00 30 2-[(Diphenylmethyl)imino]- 2540 l-methylpiperidine hydrochloride 2-1(Diphenylmethyl)imino]- 25 50l-methylpyrolidine hydrochloride 2-(Diphenylmethylimino)hexa- 50 52hydroazepine hydrochloride 2-[(DiphenylmethyUiminol- 5O 48 piperidinehydrochloride 2-[(Diphenylmethyl)imino]hexa- 50 32 hydro-I-methylazepineacid maleate Z-l(Diphenylmethyhiminolocta- I00 21 hydroazocinehydrochloride 2-[(DiphenylmethylfiminoIaza- I00 12 cyclotridecanehydrochloride 2[(Diphenylmethyl)imino]octa- 32 hydroazocinehydrochloride Hexahydro-2-[aphenyl-p-mcthoxy- 100 ISbenzyl)imino]azepine hydrochloride Hexahydro-Z-l(m-methoxy-a-phenyl- 100l l benzyl)imino]azepine hydrochloride Hexahydro-2-[(o-methoxy-a-phenyl-I00 9 bcnzyl)imino]azepine hydrochloride 2-l(p-Melhoxy-a-phenylbcnzyl)-100 47 imin0]piperidine hydrochloride 2-[(p-Butoxy-a-phenylbenzyl)- I009 iminolhexahydroazepine hydrochloride N 1 loweralkyl-OC H7)n Formula Vwith a primary amine of the following general formula in a mannersimilar to that reported by R.E. Benson and TL. Cairns in J. Am. Chem.Soc. 70, 2115-8 (1948). The symbols n and R have the meanings definedhereinbefore and lower alkyl may be methyl, ethyl or the like. Thisreaction may be carried out with or without a solvent. When a solvent isused that preferred is a lower alcohol; however, other solvents such asbenzene, toluene and the like may be used. A basic or acidic catalystsuch as a tertiary amine or hydrogen Formula VI chloride may be added tothe reaction mixture. In general it is preferred that the hydrochloridesalt of the amine be used in the reaction. The temperature of thereaction varies from 40 to 180 C, and the preferred temperature is about15-25 C. The reaction time varies from 1 hour to about 60 days beingdependent upon the temperature of the reaction, the reactant primaryamine, and more particularly on the degree of steric hindrance of theamine since highly sterically hindered amines react very slowly.

The compounds of this invention may also be prepared using a complex ofan appropriate lactam of the formula wherein n and R have the meaningsdefined hereinbefore, with phosphorous oxychloride, phosgene,borontrifluoride etherate, dimethyl sulfate, hydrogen halide or acombination of two or more such reagents. Several attempts have beenmade to formulate the structure of these complexes, and one formulationincludes the vinyl halide, that is, 2-chloro-4,5;6,7-tetrahydro-3H-azepine. However, none of the formulations have been unambiguouslyestablished. This reaction has been studied by H. Bredereck in a seriesof articles in Chem. Ber., 1953-1968, particularly in vol. 94, 2278(1961) and vol. 97, 1403 (1964). The complex formed is reacted with anappropriate primary amine described hereinabove in an aromatichydrocarbon solvent such as benzene, toluene or xylene or an alkylpolyhalide solvent such as carbon tetrachloride, chloroform, methylenechloride, dichloroethane, tetrachloroethylene or the like. The reactiontemperature is limited by the boiling point of the solvent, however, insome cases it is advantageous to carry out the reaction at roomtemperature or with cooling at to -40 C depending on the reactants.

Similarly the above reaction may be carried out by using knownthiolactim ethers such as S-methylthiocaprolactim [H. Behringer and H.Meier, 'Ann. 607, 73-91 1957 or by using thiolactams wherein the lattercase it may be advantageous to employ a catalyst such as mercury orsilver oxide or cyanide [J Gauthier and J. Renault, CR. Acad. Sci. 234,(1952)].

Also by catalytic hydrogenation of an appropriate amino-pyridinederivative as described by T. Grave, J.Am. Chem. Soc. 46, 1460 (1924),M. Friefelder et al., J. Org. Chem. 29, 3730 (1964) and L. Birkhofer,Ber. 75, 429 (1942), compounds of this invention containing 21pentamethylenimine moiety may be obtained.

The lactim others which find use in this reaction may be prepared fromcommercially available corresponding lactams by methods known in theart. For example, by reaction of an appropriate lactam with dimethylsulfate in a solvent such as benzene, toluene, xylene or the like at thereflux temperature of the solvent for 2-24 hours the correspondingO-methyl lactim ether is obtained.

The primary amines which find use in this invention are benzhydrylaminesof the following structure:

R l ormula VII R Formula VIII to benzhydrylamines either directly, forinstance by the Leuckart reaction or a variation thereof, or indirectlyby way of the oximes (1X) ri-on' formed from benzophenones andhydroxylamine, using a reducing agent such as lithium aluminum hydride,sodium in alcohol or molecular hydrogen in the presence of a noble metalcatalyst, preferably rhodium-oncharcoal. 1n the above Formulas Vll, V111and 1X, R has the meaning defined hereinbefore.

The following specific examples are illustrative of this invention.

R Formula IX EXAMPLE 1 2-(Diphenylmethylimino)hexahydroazepine chlorideA slurry of 18.3 g (0.083 mole) of benzhydrylamine hydrochloride in 25ml of O-methylcaprolactim was allowed to stand at room temperature for 3days and was stirred occasionally with a glass rod. At first the mixturebegan to solidify and samll amounts of anhydrous ethanol were added tokeep the mixture in a stirrable slurry. The mixture was then cooled. Theresulting solid was collected, washed with ether and recrystallized frommethanol-acetone to give the desired compound, m.p. 264.5265.5 C.

EXAMPLE 2 Hexahydro-2-[(oz-phenyl-p-methoxybenzyl)imino]azepinehydrochloride A. To p-methoxyphenylmagnesium bromide, prepared from 10.8g of magnesium turnings and 80.3 g of p-bromoanisole in about 180 ml ofanhydrous ether, was added dropwise a solution of 37.2 g of benzonitrilein 50 ml of anhydrous ether. The mixture was refiexed for 3 hours andallowed to stand overnight at room temperature. The resulting slurry ofketimine salt was added dropwise to 16.3 g of lithium aluminum hydrideunder 1,500 ml of anhydrous ether, and the mixture was refluxedovernight. The mixture was decomposed by adding 16.3 ml of waterfollowed by 16.3 ml of 15 percent NaOH which was followed by 48.9 ml ofwater. The mixture was stirred about 5 hours at room temperhydroature.The inorganic material was filtered off, and 250 ml of 2NHCl was addedto the filtrate which was washed with water. The resulting precipitatewas collected and recrystallized from isopropanol/water to givea-phenyl-p-methoxybenzylamine hydrochloride.

B. By the procedure of Example 1, only substituting for benzhydrylaminehydrochloride, an appropriate amount of a-phenyl-p-methoxybenzylaminehydrochloride the desired product was obtained, m.p. 224226.5 C.

EXAMPLE 3 Following the procedure of Example 2 (A) only substituting forp-methoxyphenylmagnesium bromide appropriate amounts of orm-methoxyphenylmagnesium bromide or p-n-butoxyphenylmagnesium bromidethe following compounds were prepared: a-phenyl-o-methoxybenzylaminehydrochloride, m.p. 260-26l C, oz-phenyl-m-methoxybenzylaminehydrochloride, m.p. 265-226 C (dec), a-phenyl-p-butoxybenzylaminehydrochloride, 2092l 1 C.

EXAMPLE 4 EXAMPLE 5 2-[(p-Methoxy-a-phenylbenzyl)imino]piperidinedrochloride By the procedure of Example I only substituting forbenzhydrylamine hydrochloride and O- methylcaprolactim, appropriateamounts of a-phenyl-p-methoxybenzylamine hydrochloride and O-methylvalerolactim respectively, the title compound was obtained, m.p.l84186 C.

EXAMPLE 6 2-[(Diphenylmethyl)imino]piperidine hydrochloride A mixture of100.0 g (0.455 mole) of benzhydrylamine hydrochloride, 56.6 g (0.500mole) of O- methylvalerolactim and 500 ml of methanol was refluxed for 1hr. Most of the solvent was evaporated in vacuo, 1 liter of acetone wasadded and the remaining methanol was removed as azeotrop by boilinguntil the product precipitated. Two recrystallizations frommethanol-acetone gave the title compound, m.p. 239-24- 1 C.

EXAMPLE 7" 2-[(l)iphenylmethyl)imino]pyrrolidinc hydrochloride By theprocedure of Example I, only substituting for O-methyLcaprolactim anappropriate amount of O-methyl-y-butyrolactim the title compound wasobtained, m.p. 2l7-2l8.5 C.

EXAMPLE 8 2-[(Diphenylmethyl)imino]-l-methylpiperidine hydrochloride To25.3 g (0.223 mole) of N-methylpiperid-2-one in 250 ml of benzene wasadded 34.1 g (0.223 mole) of phosphorus oxychloride over 30 minutes. Themixture was stirred at room temperature for 4 hours after which 40.8 g(0.223 mole) of benzhydrylamine was added. The reaction mixture wasstirred at room temperature for l hour and refluxed for 4 hours thenallowed to stand overnight. The resulting precipitate was washed withbenzene, and the benzene wash was extracted with aqueous 2N HCl andcombined with the precipitate. The combined fractions were made alkalinewith 2N NaOl-l, extracted into ether/methylene chloride, dried andrecrystallized from isopropanol to give 2-[(diphenylmethyl)-imino]-l-methylpiperidine which was subsequentlyconverted to the hydrochloride salt, m.p. 225-228 C.

EXAMPLE 9 By the procedure of Example 8 only substituting forN-methyl-piperid-2-one an appropriate amount of enantholactam,caprylolactam, azacyclotridecan-Z-one or N-methylpyrrolid-Z-one thefollowing compounds were prepared:

2-[(diphenylmethyl)imino]octahydroazocine hydrochloride, m.p. 285-286 C,2-[(diphenylmethyl)imino]octahydroazocine hydrochloride, m.p. 283285 C,2-[ diphenylmethyl )imino azacyclotridecane hydrochloride, m.p. l40-l65C, 2-[(diphenylmethyl)imino]-l-methylpyrrolidine drochloride, m.p.l94l95 C.

EXAMPLE l0 EXAMPLE 1 l 2-[(a-phenyl-p-methoxybenzyl )imino]- lmethylpyrrolidine hydrochloride By the procedure of Example 8 onlysubstituting for benzhydrylamine and N-methylpiperid-2-one appropriateamounts of a-phenyl-p-methoxybenzylamine hydrochloride andN-methylpyrrolid-Z-one the title compound is obtained.

EXA'MPLE 12 An illustrative composition for tablets is as follows:

Per Tablet (a) 2l(diphcnylmcthyhiminolpiperidinc hydrochloride l00.0 mg(h) wheat illurch 15.0 mg (c) lactose 33.5 mg (d) magnesium slcuralc 1.5mg

A granulation obtained upon mixing lactose with the starch andgranulated starch paste is dried, screened and mixed with the activeingredient and magnesium stearate. The mixture is compressed in tabletsweighing 150 mg each.

EXAMPLE 13 An illustrative composition for a parenteral injection is thefollowing wherein the quantities are on a weight to volume basis.

2-l(Diphenylmethyl)imino]-lmcthylpiperidine hydrochloride l mg. (b)Sodium chloride q.s. (c) Water for injection to make l0 ml.

The composition is prepared by dissolving the active ingredient andsufficient sodium chloride in water for injection to render the solutionisotonic. The composi tion may be dispensed in a single ampulecontaining 100 mg. of the active ingredient for multiple dosage or in IQampules for a single dosage.

EXAMPLE 14 An illustrative composition for hard gelatin capsules is asfollows:

Per Capsule hexahydro-ZI(a-phenyl-pmethoxybenzyl- )iminol-azepinehydrochloride 200 mg. (b) Talc 35 mg.

The formulation is prepared by passing the dry powders of (a) and (b)through a fine mesh screen and mixing them well. The powder is thenfilled into No. 0 hard gelatin capsules at a net fill of 235 mg. percapsule.

EXAMPLE 15 An illustrative composition for pills is as follows:

Per Fill (a) 2l(Diphenylmethyhiminolpipcridine hydrochloride l00 mg (b)Starch, com 90 mg. (c) Liquid glucose l0 mg.

The pills are prepared by blending the active ingredient and starchand-then adding the liquid glucose with thorough kneading to form aplastic mass. The pills are then cut and formed from the plastic pillmass.

We claim:

1. A method of inducing a hypoglycemic response in a hyperglycemicpatient which comprises administering to said patient an effectivehypoglycemic amount of a compound having the formula wherein R isselected from hydrogen or lower alkoxy of from one to six carbon atoms;R is selected from hydrogen or lower alkyl of from one to four carbonatmos; n is 4; or a pharmaceutically acceptable acid addition salt ofsaid compound.

2. A method as claimed in claim 1 wherein the effective amount ofcompound administered is from l mg/kg to 100 mg/kg of body weight of thepatient.

3. A method as claimed in claim 2 wherein said compound is administeredin dosage units containing from 25 mg to 500 mg of said compound intablets which are taken from 1 to 4 times daily.

4. A method as claimed in claim 2 wherein said compound is administeredorally.

5. A method as claimed in claim 2 wherein said compound is administeredparentcrally.

6. A method as claimed in claim 2 wherein the compound has the formulawherein R is selected from hydrogen or lower alkoxy of from one to sixcarbon atoms; n is 4; or a pharmaceutically acceptable acid additionsalt of said compound. 7. A method as claimed in claim 6 wherein thecompound is 2-[(diphenylmethyl)imino]piperidine hydrochloride.

@2 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.51,7 5, Dated January 1, 1974 I ventor(s) J. Martin Grisar and Themes R.Blohm It is certified that error appears in the above-identified patentv and that said Letters Patent are hereby corrected as shown below:

Column 6, line 45, "samll" should read "small". Column 7, l ine 22, "265-226C." should read "265-266C. column 7, line 57, "imin01hydochloridehydrocloride should read "imlno]hexahydroazepine hydrochloride". 1

Signed and: sealed this 9th day of July 1971+.

(SEAL) Attest:

MCCOY M. GIBSON, JR. C MARSI IALL DANN I Attesting Officer Commissionerof Patents

2. A method as claimed in claim 1 wherein the effective amount ofcompound administered is from 1 mg/kg to 100 mg/kg of body weight of thepatient.
 3. A method as claimed in claim 2 wherein said compound isadministered in dosage units containing from 25 mg to 500 mg of saidcompound in tablets which are taken from 1 to 4 times daily.
 4. A methodas claimed in claim 2 wherein said compound is administered orally.
 5. Amethod as claimed in claim 2 wherein said compound is administeredparenterally.
 6. A method as claimed in claim 2 wherein the compound hasthe formula
 7. A method as claimed in claim 6 wherein the compound is2-((diphenylmethyl)imino)piperidine hydrochloride.